bims-mibica 2023-09-10 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2023‒09‒10
twenty-one papers selected by
Kelsey Fisher-Wellman, East Carolina University

Glycolytic Metabolon Assembly on Mitochondria via Hexokinase O-GlcNAcylation Promotes Metabolic Efficiency.
Inhibition of mitochondrial fatty acid β-oxidation activates mTORC1 pathway and protein synthesis via Gcn5-dependent acetylation of raptor in zebrafish.
Fatty acid oxidation regulates cellular senescence by modulating the autophagy-SIRT1 axis.
Regulation with cell size ensures mitochondrial DNA homeostasis during cell growth.
Antigen receptor stimulation induces purifying selection against pathogenic mitochondrial tRNA mutations.
Knockdown of PGC1α suppresses dysplastic oral keratinocytes proliferation through reprogramming energy metabolism.
Ets1 facilitates EMT/invasion through Drp1-mediated mitochondrial fragmentation in ovarian cancer.
C17orf80 binds the mitochondrial genome to promote its replication.
LINC00116-encoded microprotein mitoregulin regulates fatty acid metabolism at the mitochondrial outer membrane.
Targeting the metabolic enzyme PGAM2 overcomes enzalutamide resistance in castration-resistant prostate cancer by inhibiting BCL2 signaling.
A mitochondrial EglN1-AMPKα axis drives breast cancer progression by enhancing metabolic adaptation to hypoxic stress.
Metabolic Alterations in Canine Mammary Tumors.
Case Report: Tumor-to-tumor metastasis with prostate cancer metastatic to lung cancer: the first reported case.
Creatine supplementation enhances anti-tumor immunity by promoting adenosine triphosphate production in macrophages.
Serine-associated one-carbon metabolic reprogramming: a new anti-cancer therapeutic strategy.
Mitochondrial reactive oxygen species modify extracellular vesicles secretion rate.
Loss of attachment promotes proline accumulation and excretion in cancer cells.
Mitochondria in oral cancer stem cells: Unraveling the potential drug targets for new and old drugs.
Intact mitochondrial function in the setting of telomere-induced senescence.
Inhibition of TCA cycle improves the anti-PD-1 immunotherapy efficacy in melanoma cells via ATF3-mediated PD-L1 expression and glycolysis.
MitoQ combats tumor cell progression in Ehrlich ascites carcinoma mice: A crosstalk between mitochondrial oxidative status, mitophagy, and NF-κB signaling.

bioRxiv. 2023 Aug 26. pii: 2023.08.26.554955. [Epub ahead of print]

Glycolytic Metabolon Assembly on Mitochondria via Hexokinase O-GlcNAcylation Promotes Metabolic Efficiency.

Haoming Wang, John Vant, Youjun Wu, Richard Sánchez, Mary Lauren Micou, Andrew Zhang, Vincent Luczak, Seungyoon Blenda Yu, Mirna Jabbo, Seokjun Yoon, Ahmed Abdallah Abushawish, Majid Ghassemian, Eric Griffis, Marc Hammarlund, Abhishek Singharoy, Gulcin Pekkurnaz.

Glucose is the primary cellular energy substrate and its metabolism via glycolysis is initiated by the rate-limiting enzyme Hexokinase (HK). In energy-demanding tissues like the brain, HK1 is the prominent isoform, primarily localized on mitochondria, crucial for the efficient coupling of glycolysis and oxidative phosphorylation, thereby ensuring optimal energy generation. Here, we reveal a novel regulatory mechanism whereby metabolic sensor enzyme O-GlcNAc transferase (OGT) modulates HK1 activity and its mitochondrial association. OGT catalyzes reversible O-GlcNAcylation, a post-translational modification, influenced by glucose flux-mediated intracellular UDP-GlcNAc concentrations. Dynamic O-GlcNAcylation of HK1's regulatory domain occurs with increased OGT activity, promoting glycolytic metabolon assembly on the outer mitochondrial membrane. This modification enhances HK1's mitochondrial localization, orchestrating glycolytic and mitochondrial ATP production. Mutations in HK1's O-GlcNAcylation site reduce ATP generation, affecting presynaptic vesicle release in neurons. Our findings reveal a new pathway linking neuronal metabolism to mitochondrial function through OGT and glycolytic metabolon formation, and provide important insight into the previously unknown metabolism plasticity mechanism.

DOI: https://doi.org/10.1101/2023.08.26.554955
J Biol Chem. 2023 Sep 01. pii: S0021-9258(23)02248-2. [Epub ahead of print] 105220

Inhibition of mitochondrial fatty acid β-oxidation activates mTORC1 pathway and protein synthesis via Gcn5-dependent acetylation of raptor in zebrafish.

Wen-Hao Zhou, Yuan Luo, Rui-Xin Li, Pascal Degrace, Tony Jourdan, Fang Qiao, Li-Qiao Chen, Mei-Ling Zhang, Zhen-Yu Du.

  Pharmacological inhibition of mitochondrial fatty acid oxidation (FAO) has been clinically used to alleviate certain metabolic diseases by remodeling cellular metabolism. However, mitochondrial FAO inhibition also leads to mTORC1 activation-related protein synthesis and tissue hypertrophy, but the mechanism remains unclear. Here, by using a mitochondrial FAO inhibitor (Mildronate or Etomoxir) or knocking out carnitine palmitoyltransferase-1, we revealed that mitochondrial FAO inhibition activated the mTORC1 pathway through Gcn5-dependent Raptor acetylation. Mitochondrial FAO inhibition significantly promoted glucose catabolism and increased intracellular acetyl-CoA levels. In response to the increased intracellular acetyl-CoA, acetyltransferase Gcn5 activated mTORC1 by catalyzing Raptor acetylation through direct interaction. Further investigation also screened Raptor deacetylases HDAC class II and identified HDAC7 as a potential regulator of Raptor. These results provide a possible mechanistic explanation for the mTORC1 activation after mitochondrial FAO inhibition and also bring light to reveal the roles of nutrient metabolic remodeling in regulating protein acetylation by affecting acetyl-CoA production.

Keywords:  Gcn5; Raptor; acetyl-CoA; mTORC1; mitochondrial FAO inhibition

DOI:  https://doi.org/10.1016/j.jbc.2023.105220
BMB Rep. 2023 Sep 08. pii: 5938. [Epub ahead of print]

Fatty acid oxidation regulates cellular senescence by modulating the autophagy-SIRT1 axis.

Seungyeon Yang, Subin Moon, Soojung Claire Hur, Seung Min Jeong.

Senescence, a cellular process through which damaged or dysfunctional cells suppress their cell cycle, contributes to aging or age-related functional declines. Cell metabolism has been closely correlated with aging processes and it is widely recognized that metabolic changes underlie cellular alterations with aging. Here, we report that fatty acid oxidation (FAO) serves as a critical regulator of cellular senescence and uncover the underlying mechanism by which FAO inhibition induces senescence. Pharmacological or genetic ablation of FAO results in a p53-dependent induction of cellular senescence in human fibroblasts, whereas enhancing FAO suppresses replicative senescence. We find that FAO inhibition promotes cellular senescence through acetyl-CoA, independent of energy depletion. Mechanistically, the increased formation of autophagosome following FAO inhibition leads to a reduction in SIRT1 protein levels, thereby contributing to senescence induction. Finally, we find that the inhibition of autophagy or the enforced expression of SIRT1 can rescue the induction of senescence as a result of FAO inhibition. Collectively, our study reveals a distinctive role for the FAO-autophagy-SIRT1 axis in the regulation of cellular senescence.
Nat Struct Mol Biol. 2023 Sep 07.

Regulation with cell size ensures mitochondrial DNA homeostasis during cell growth.

Anika Seel, Francesco Padovani, Moritz Mayer, Alissa Finster, Daniela Bureik, Felix Thoma, Christof Osman, Till Klecker, Kurt M Schmoller.

To maintain stable DNA concentrations, proliferating cells need to coordinate DNA replication with cell growth. For nuclear DNA, eukaryotic cells achieve this by coupling DNA replication to cell-cycle progression, ensuring that DNA is doubled exactly once per cell cycle. By contrast, mitochondrial DNA replication is typically not strictly coupled to the cell cycle, leaving the open question of how cells maintain the correct amount of mitochondrial DNA during cell growth. Here, we show that in budding yeast, mitochondrial DNA copy number increases with cell volume, both in asynchronously cycling populations and during G1 arrest. Our findings suggest that cell-volume-dependent mitochondrial DNA maintenance is achieved through nuclear-encoded limiting factors, including the mitochondrial DNA polymerase Mip1 and the packaging factor Abf2, whose amount increases in proportion to cell volume. By directly linking mitochondrial DNA maintenance to nuclear protein synthesis and thus cell growth, constant mitochondrial DNA concentrations can be robustly maintained without a need for cell-cycle-dependent regulation.

DOI: https://doi.org/10.1038/s41594-023-01091-8
JCI Insight. 2023 Sep 08. pii: e167656. [Epub ahead of print]8(17):

Antigen receptor stimulation induces purifying selection against pathogenic mitochondrial tRNA mutations.

Jingdian Zhang, Camilla Koolmeister, Jinming Han, Roberta Filograna, Leo Hanke, Monika Àdori, Daniel J Sheward, Sina Teifel, Shreekara Gopalakrishna, Qiuya Shao, Yong Liu, Keying Zhu, Robert A Harris, Gerald McInerney, Ben Murrell, Mike Aoun, Liselotte Bäckdahl, Rikard Holmdahl, Marcin Pekalski, Anna Wedell, Martin Engvall, Anna Wredenberg, Gunilla B Karlsson Hedestam, Xaquin Castro Dopico, Joanna Rorbach.

  Pathogenic mutations in mitochondrial (mt) tRNA genes that compromise oxidative phosphorylation (OXPHOS) exhibit heteroplasmy and cause a range of multisyndromic conditions. Although mitochondrial disease patients are known to suffer from abnormal immune responses, how heteroplasmic mtDNA mutations affect the immune system at the molecular level is largely unknown. Here, in mice carrying pathogenic C5024T in mt-tRNAAla and in patients with mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS) syndrome carrying A3243G in mt-tRNALeu, we found memory T and B cells to have lower pathogenic mtDNA mutation burdens than their antigen-inexperienced naive counterparts, including after vaccination. Pathogenic burden reduction was less pronounced in myeloid compared with lymphoid lineages, despite C5024T compromising macrophage OXPHOS capacity. Rapid dilution of the C5024T mutation in T and B cell cultures could be induced by antigen receptor-triggered proliferation and was accelerated by metabolic stress conditions. Furthermore, we found C5024T to dysregulate CD8+ T cell metabolic remodeling and IFN-γ production after activation. Together, our data illustrate that the generation of memory lymphocytes shapes the mtDNA landscape, wherein pathogenic variants dysregulate the immune response.

Keywords:  Adaptive immunity; Immunology; Metabolism; Mitochondria

DOI:  https://doi.org/10.1172/jci.insight.167656
Int J Oral Sci. 2023 09 04. 15(1): 37

Knockdown of PGC1α suppresses dysplastic oral keratinocytes proliferation through reprogramming energy metabolism.

Yunkun Liu, Nengwen Huang, Xianghe Qiao, Zhiyu Gu, Yongzhi Wu, Jinjin Li, Chengzhou Wu, Bo Li, Longjiang Li.

Oral potentially malignant disorders (OPMDs) are precursors of oral squamous cell carcinoma (OSCC). Deregulated cellular energy metabolism is a critical hallmark of cancer cells. Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC1α) plays vital role in mitochondrial energy metabolism. However, the molecular mechanism of PGC1α on OPMDs progression is less unclear. Therefore, we investigated the effects of knockdown PGC1α on human dysplastic oral keratinocytes (DOKs) comprehensively, including cell proliferation, cell cycle, apoptosis, xenograft tumor, mitochondrial DNA (mtDNA), mitochondrial electron transport chain complexes (ETC), reactive oxygen species (ROS), oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and glucose uptake. We found that knockdown PGC1α significantly inhibited the proliferation of DOKs in vitro and tumor growth in vivo, induced S-phase arrest, and suppressed PI3K/Akt signaling pathway without affecting cell apoptosis. Mechanistically, downregulated of PGC1α decreased mtDNA, ETC, and OCR, while enhancing ROS, glucose uptake, ECAR, and glycolysis by regulating lactate dehydrogenase A (LDHA). Moreover, SR18292 (an inhibitor of PGC1α) induced oxidative phosphorylation dysfunction of DOKs and declined DOK xenograft tumor progression. Thus, our work suggests that PGC1α plays a crucial role in cell proliferation by reprograming energy metabolism and interfering with energy metabolism, acting as a potential therapeutic target for OPMDs.

DOI: https://doi.org/10.1038/s41368-023-00242-3
iScience. 2023 Sep 15. 26(9): 107537

Ets1 facilitates EMT/invasion through Drp1-mediated mitochondrial fragmentation in ovarian cancer.

Deepshikha Ghosh, Suman Pakhira, Damayanti Das Ghosh, Susanta Roychoudhury, Sib Sankar Roy.

  Ovarian cancer has sustained as a major cause of cancer-related female mortality owing to its aggressive nature and a dearth of early detection markers. Ets1 oncoprotein, a transcription factor belonging to the Ets family, is a well-established promoter of epithelial to mesenchymal transition (EMT) and a prospective malignancy marker in ovarian cancer. Our study establishes Ets1 as a regulator of mitochondrial fission-fusion dynamics through Drp1 augmentation via direct binding at DNM1L (DRP1) promoter. Ets1 overexpression-mediated Drp1 increment resulted in mitochondrial load reduction and compromised OXPHOS Complex 5 (ATP synthase) expression, facilitating a greater reliance on glycolysis over OXPHOS. Furthermore, our work demonstrates that inhibition of mitochondrial fission through molecular or pharmacological inhibition of Drp1 successfully mitigates Ets1-associated EMT in both in vitro and in vivo syngeneic mice model. Collectively, our data highlight the role of Drp1-mediated mitochondrial fragmentation in driving Ets1-mediated bioenergetic alterations and EMT/invasion in ovarian cancer.

Keywords:  Cancer; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2023.107537
J Cell Biol. 2023 Oct 02. pii: e202302037. [Epub ahead of print]222(10):

C17orf80 binds the mitochondrial genome to promote its replication.

Hao Wu, Wenshuo Zhang, Fengli Xu, Kun Peng, Xiaoyu Liu, Wanqiu Ding, Qi Ma, Heping Cheng, Xianhua Wang.

Serving as the power plant and signaling hub of a cell, mitochondria contain their own genome which encodes proteins essential for energy metabolism and forms DNA-protein assemblies called nucleoids. Mitochondrial DNA (mtDNA) exists in multiple copies within each cell ranging from hundreds to tens of thousands. Maintaining mtDNA homeostasis is vital for healthy cells, and its dysregulation causes multiple human diseases. However, the players involved in regulating mtDNA maintenance are largely unknown though the core components of its replication machinery have been characterized. Here, we identify C17orf80, a functionally uncharacterized protein, as a critical player in maintaining mtDNA homeostasis. C17orf80 primarily localizes to mitochondrial nucleoid foci and exhibits robust double-stranded DNA binding activity throughout the mitochondrial genome, thus constituting a bona fide new mitochondrial nucleoid protein. It controls mtDNA levels by promoting mtDNA replication and plays important roles in mitochondrial metabolism and cell proliferation. Our findings provide a potential target for therapeutics of human diseases associated with defective mtDNA control.

DOI: https://doi.org/10.1083/jcb.202302037
iScience. 2023 Sep 15. 26(9): 107558

LINC00116-encoded microprotein mitoregulin regulates fatty acid metabolism at the mitochondrial outer membrane.

Shan Zhang, Yabo Guo, Gio Fidelito, David R L Robinson, Chao Liang, Radiance Lim, Zoë Bichler, Ruiyang Guo, Gaoqi Wu, He Xu, Quan D Zhou, Brijesh K Singh, Paul Yen, Dennis Kappei, David A Stroud, Lena Ho.

  LINC00116 encodes a microprotein first identified as Mitoregulin (MTLN), where it was reported to localize to the inner membrane of mitochondria to regulate fatty acid oxidation and oxidative phosphorylation. These initial discoveries were followed by reports with differing findings about its molecular functions and submitochondrial localization. To clarify the apparent discrepancies, we constructed multiple orthogonal methods of determining the localization of MTLN, including split GFP-based reporters that enable efficient and reliable topology analyses for microproteins. These methods unequivocally demonstrate MTLN primarily localizes to the outer membrane of mitochondria, where it interacts with enzymes of fatty acid metabolism including CPT1B and CYB5B. Loss of MTLN causes the accumulation of very long-chain fatty acids (VLCFAs), especially docosahexaenoic acid (DHA). Intriguingly, loss of MTLN protects mice against western diet/fructose-induced insulin-resistance, suggests a protective effect of VLCFAs in this context. MTLN thus serves as an attractive target to control the catabolism of VLCFAs.

Keywords:  Biochemistry; Biological sciences; Cell biology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2023.107558
Cancer Res. 2023 Sep 07.

Targeting the metabolic enzyme PGAM2 overcomes enzalutamide resistance in castration-resistant prostate cancer by inhibiting BCL2 signaling.

Zhen Li, Kang Ning, Diwei Zhao, Zhaohui Zhou, Junliang Zhao, Xingbo Long, Zhenyu Yang, Dong Chen, Xinyang Cai, Lexuan Hong, Luyao Zhang, Fangjian Zhou, Jun Wang, Yonghong Li.

The next-generation androgen receptor (AR) inhibitor enzalutamide (ENZ) is the mainstay treatment for metastatic prostate cancer. Unfortunately, resistance occurs rapidly in most patients, and once resistance occurs treatment options are limited. Therefore, there is an urgent need to identify effective targets to overcome ENZ resistance. Here, using a genome-wide CRISPR-Cas9 library screen, we found that targeting a glycolytic enzyme, phosphoglycerate mutase PGAM2, significantly enhanced the sensitivity of ENZ-resistant prostate cancer cells to ENZ both in vivo and in vitro. Inhibition of PGAM2 together with ENZ treatment triggered apoptosis by decreasing levels of the anti-apoptotic protein BCL-xL and increasing activity of the pro-apoptotic protein BAD. Mechanistically, PGAM2 bound to 14-3-3ζ and promoted its interaction with phosphorylated BAD, resulting in activation of BCL-xL and subsequent resistance to ENZ-induced apoptosis. In addition, high PGAM2 expression, which is transcriptionally regulated by AR, was associated with shorter survival and rapid development of ENZ resistance in prostate cancer patients. Together, these findings provide evidence of a non-metabolic function of PGAM2 in promoting ENZ resistance and identify PGAM2 inhibition as a promising therapeutic strategy for ENZ-resistant prostate cancer.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-0308
EMBO J. 2023 Sep 04. e113743

A mitochondrial EglN1-AMPKα axis drives breast cancer progression by enhancing metabolic adaptation to hypoxic stress.

Weiwei Jiang, Mengyao Zhang, Chuan Gao, Chaojun Yan, Ronghui Gao, Ziwei He, Xin Wei, Jingjing Xiong, Zilun Ruan, Qian Yang, Jinpeng Li, Qifang Li, Ziyi Zhong, Mengna Zhang, Qianqian Yuan, Hankun Hu, Shuang Wang, Ming-Ming Hu, Cheguo Cai, Gao-Song Wu, Chao Jiang, Ya-Lin Zhang, Chen-Song Zhang, Jing Zhang.

  Mitochondria play essential roles in cancer cell adaptation to hypoxia, but the underlying mechanisms remain elusive. Through mitochondrial proteomic profiling, we here find that the prolyl hydroxylase EglN1 (PHD2) accumulates on mitochondria under hypoxia. EglN1 substrate-binding region in the β2β3 loop is responsible for its mitochondrial translocation and contributes to breast tumor growth. Furthermore, we identify AMP-activated protein kinase alpha (AMPKα) as an EglN1 substrate on mitochondria. The EglN1-AMPKα interaction is essential for their mutual mitochondrial translocation. After EglN1 prolyl-hydroxylates AMPKα under normoxia, they rapidly dissociate following prolyl-hydroxylation, leading to their immediate release from mitochondria. In contrast, hypoxia results in constant EglN1-AMPKα interaction and their accumulation on mitochondria, leading to the formation of a Ca2+ /calmodulin-dependent protein kinase 2 (CaMKK2)-EglN1-AMPKα complex to activate AMPKα phosphorylation, ensuring metabolic homeostasis and breast tumor growth. Our findings identify EglN1 as an oxygen-sensitive metabolic checkpoint signaling hypoxic stress to mitochondria through its β2β3 loop region, suggesting a potential therapeutic target for breast cancer.

Keywords:  AMPKα; EglN1; hypoxia; metabolic homeostasis; mitochondrial translocation

DOI:  https://doi.org/10.15252/embj.2023113743
Animals (Basel). 2023 Aug 30. pii: 2757. [Epub ahead of print]13(17):

Metabolic Alterations in Canine Mammary Tumors.

Guilherme Henrique Tamarindo, Adriana Alonso Novais, Luiz Gustavo Almeida Chuffa, Debora Aparecida Pires Campos Zuccari.

  Canine mammary tumors (CMTs) are among the most common diseases in female dogs and share similarities with human breast cancer, which makes these animals a model for comparative oncology studies. In these tumors, metabolic reprogramming is known as a hallmark of carcinogenesis whereby cells undergo adjustments to meet the high bioenergetic and biosynthetic demands of rapidly proliferating cells. However, such alterations are also vulnerabilities that may serve as a therapeutic strategy, which has mostly been tested in human clinical trials but is poorly explored in CMTs. In this dedicated review, we compiled the metabolic changes described for CMTs, emphasizing the metabolism of carbohydrates, amino acids, lipids, and mitochondrial functions. We observed key factors associated with the presence and aggressiveness of CMTs, such as an increase in glucose uptake followed by enhanced anaerobic glycolysis via the upregulation of glycolytic enzymes, changes in glutamine catabolism due to the overexpression of glutaminases, increased fatty acid oxidation, and distinct effects depending on lipid saturation, in addition to mitochondrial DNA, which is a hotspot for mutations. Therefore, more attention should be paid to this topic given that targeting metabolic fragilities could improve the outcome of CMTs.

Keywords:  amino acids; cancer; canine mammary tumors; glucose; lipids; metabolic reprogramming; metabolism; mitochondria

DOI:  https://doi.org/10.3390/ani13172757
Front Oncol. 2023 ;13 1238331

Case Report: Tumor-to-tumor metastasis with prostate cancer metastatic to lung cancer: the first reported case.

Shiyue Liu, Hong Li, Youhong Dong, Dongdong Zhang.

  Tumor-to-tumor metastasis (TTM) occurs rarely in tumor progression, but this event has significant clinical implications. Although the impact of TTM on patient prognosis and survival has been increasingly recognized, understanding of TTM biology and treatment is limited. Prostate cancer is among the most common malignancies threatening male health. Prostate cancer can potentially metastasize to primary lung Cancer; however, this is an exceedingly rare event. We here report for the first time a case of TTM from a prostate cancer to a coexisting primary lung cancer.

Keywords:  adenocarcinoma; lung cancer; metastases; prostate cancer; tumor-to-tumor metastasis

DOI:  https://doi.org/10.3389/fonc.2023.1238331
Front Immunol. 2023 ;14 1176956

Creatine supplementation enhances anti-tumor immunity by promoting adenosine triphosphate production in macrophages.

Zhenzi Peng, Suguru Saito.

  Creatine is an indispensable organic compound utilized in physiological environments; however, its role in immunity is still poorly understood. Here, we show that creatine supplementation enhances anti-tumor immunity through the functional upregulation of macrophages by increasing adenosine triphosphate (ATP) production. Creatine supplementation significantly suppressed B16-F10-originated tumor growth in mice compared with the control treatment. Under these conditions, intratumor macrophages polarized towards the M1 phenotype rather than the M2 phenotype, and there was an increase in tumor antigen-specific CD8+ T cells in the mice. The cytokine production and antigen-presenting activity in the macrophages were enhanced by creatine supplementation, resulting in a substantial increase in tumor antigen-specific CD8+ T cells. ATP upregulation was achieved through the cytosolic phosphocreatine (PCr) system via extracellular creatine uptake, rather than through glycolysis and mitochondrial oxidative phosphorylation in the macrophages. Blockade of the creatine transporter (CrT) failed to upregulate ATP and enhance the immunological activity of macrophages in creatine supplementation, which also impaired CD8+ T cell activity. Consequently, CrT blockade failed to suppress tumor growth in the creatine-supplemented mice. Thus, creatine is an important nutrient that promotes macrophage function by increasing ATP levels, ultimately contributing to enhanced anti-tumor immunity orchestrated by CD8+ T cells.

Keywords:  ATP; CD8+ T cells; anti-tumor immunity; creatine; macrophages

DOI:  https://doi.org/10.3389/fimmu.2023.1176956
Front Oncol. 2023 ;13 1184626

Serine-associated one-carbon metabolic reprogramming: a new anti-cancer therapeutic strategy.

Jing Zhang, Jian Bai, Chen Gong, Jianhua Wang, Yi Cheng, Jing Zhao, Huihua Xiong.

  Tumour metabolism is a major focus of cancer research, and metabolic reprogramming is an important feature of malignant tumours. Serine is an important non-essential amino acid, which is a main resource of one-carbon units in tumours. Cancer cells proliferate more than normal cells and require more serine for proliferation. The cancer-related genes that are involved in serine metabolism also show changes corresponding to metabolic alterations. Here, we reviewed the serine-associated one-carbon metabolism and its potential as a target for anti-tumour therapeutic strategies.

Keywords:  SERINE; immunotherapy; metabolism reprogramming; molecular targeted therapy; one-carbon units

DOI:  https://doi.org/10.3389/fonc.2023.1184626
FASEB Bioadv. 2023 Sep;5(9): 355-366

Mitochondrial reactive oxygen species modify extracellular vesicles secretion rate.

Mikkel Ø Nørgård, Philip M Lund, Nazmie Kalisi, Thomas L Andresen, Jannik B Larsen, Stefan Vogel, Per Svenningsen.

  Extracellular vesicle (EV) secretion rate is stimulated by hypoxia that causes increased reactive oxygen species (ROS) production by the mitochondrial electron transport chain (ETC) and hypoxia-induced factor (HIF)-1 signaling; however, their contribution to the increased EV secretion rate is unknown. We found that the EV marker secretion rate in our EV reporter cell line CD9truc-EGFP was unaffected by the HIF-1α stabilizer roxadustat; yet, ETC stimulation by dichloroacetic acid (DCA) significantly increased EV secretion. The DCA-induced EV secretion was blocked by the antioxidant TEMPO and rotenone, an inhibitor of the ETC's Complex I. Under hypoxic conditions, the limited oxygen reduction impedes the ETC's Complex III. To mimic this, we inhibited Complex III with antimycin A, which increased ROS-dependent EV secretion. The electron transport between Complex I and III is accomplished by coenzyme Q created by the mevalonate pathway and tyrosine metabolites. Blocking an early step in the mevalonate pathway using pitavastatin augmented the DCA-induced EV secretion, and 4-nitrobenzoate-an inhibitor of the condensation of the mevalonate pathway with tyrosine metabolites-increased ROS-dependent EV secretion. Our findings indicate that hypoxia-mimetics targeting the ETC modify EV secretion and that ROS produced by the ETC is a potent stimulus for EV secretion.

Keywords:  cancer; electron transport chain; exercise; hypoxia; kidney; late endosome; multivesicular body

DOI:  https://doi.org/10.1096/fba.2023-00053
Sci Adv. 2023 Sep 08. 9(36): eadh2023

Loss of attachment promotes proline accumulation and excretion in cancer cells.

Steven E Pilley, Marc Hennequart, Anke Vandekeere, Julianna Blagih, Nathalie M Legrave, Sarah-Maria Fendt, Karen H Vousden, Christiaan F Labuschagne.

Previous studies have revealed a role for proline metabolism in supporting cancer development and metastasis. In this study, we show that many cancer cells respond to loss of attachment by accumulating and secreting proline. Detached cells display reduced proliferation accompanied by a general decrease in overall protein production and de novo amino acid synthesis compared to attached cells. However, proline synthesis was maintained under detached conditions. Furthermore, while overall proline incorporation into proteins was lower in detached cells compared to other amino acids, there was an increased production of the proline-rich protein collagen. The increased excretion of proline from detached cells was also shown to be used by macrophages, an abundant and important component of the tumor microenvironment. Our study suggests that detachment induced accumulation and secretion of proline may contribute to tumor progression by supporting increased production of extracellular matrix and providing proline to surrounding stromal cells.

DOI: https://doi.org/10.1126/sciadv.adh2023
Life Sci. 2023 Sep 01. pii: S0024-3205(23)00700-2. [Epub ahead of print]331 122065

Mitochondria in oral cancer stem cells: Unraveling the potential drug targets for new and old drugs.

Ivonne Olmedo, Daniela Martínez, Javiera Carrasco-Rojas, José A Jara.

  Head and neck cancer is a major health problem worldwide, with most cases arising in the oral cavity. Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer, accounting for over 90% of all cases. Compared to other types of cancer, OSCC, has the worse prognosis, with a 5-year survival rate of 50%. Additionally, OSCC is characterized by a high rate of resistance to chemotherapy treatment, which may be partly explained by the presence of cancer stem cells (CSC) subpopulation. CSC can adapt to harmful environmental condition and are highly resistant to both chemotherapy and radiotherapy treatments, thus contributing to tumor relapse. The aim of this review is to highlight the role of mitochondria in oral CSC as a potential target for oral cancer treatment. For this purpose, we reviewed some fundamental aspects of the most validated protein markers of stemness, autophagy, the mitochondrial function and energy metabolism in oral CSC. Moreover, a discussion will be made on why energy metabolism, especially oxidative phosphorylation in CSC, may offer such a diverse source of original pharmacological target for new drugs. Finally, we will describe some drugs able to disturb mitochondrial function, with emphasis on those aimed to interrupt the electron transport chain function, as novel therapeutic strategies in multidrug-resistant oral CSC. The reutilization of old drugs approved for clinical use as new antineoplastics, in cancer treatment, is also matter of revision.

Keywords:  Cancer stem cells; Drugs target; Mitochondria metabolism; Oral cancer

DOI:  https://doi.org/10.1016/j.lfs.2023.122065
Aging Cell. 2023 Sep 08. e13941

Intact mitochondrial function in the setting of telomere-induced senescence.

Daniel I Sullivan, Fiona M Bello, Agustin Gil Silva, Kevin M Redding, Luca Giordano, Angela M Hinchie, Kelly E Loughridge, Ana L Mora, Melanie Königshoff, Brett A Kaufman, Michael J Jurczak, Jonathan K Alder.

  Mitochondria play essential roles in metabolic support and signaling within all cells. Congenital and acquired defects in mitochondria are responsible for several pathologies, including premature entrance to cellar senescence. Conversely, we examined the consequences of dysfunctional telomere-driven cellular senescence on mitochondrial biogenesis and function. We drove senescence in vitro and in vivo by deleting the telomere-binding protein TRF2 in fibroblasts and hepatocytes, respectively. Deletion of TRF2 led to a robust DNA damage response, global changes in transcription, and induction of cellular senescence. In vitro, senescent cells had significant increases in mitochondrial respiratory capacity driven by increased cellular and mitochondrial volume. Hepatocytes with dysfunctional telomeres maintained their mitochondrial respiratory capacity in vivo, whether measured in intact cells or purified mitochondria. Induction of senescence led to the upregulation of overlapping and distinct genes in fibroblasts and hepatocytes, but transcripts related to mitochondria were preserved. Our results support that mitochondrial function and activity are preserved in telomere dysfunction-induced senescence, which may facilitate continued cellular functions.

Keywords:  SASP; shelterin; telomerase

DOI:  https://doi.org/10.1111/acel.13941
J Immunother Cancer. 2023 Sep;pii: e007146. [Epub ahead of print]11(9):

Inhibition of TCA cycle improves the anti-PD-1 immunotherapy efficacy in melanoma cells via ATF3-mediated PD-L1 expression and glycolysis.

Nian Liu, Mingjie Yan, Qian Tao, Jie Wu, Jing Chen, Xiang Chen, Cong Peng.

  BACKGROUND: anti-Programmed Death-1 (anti-PD-1) immunotherapy has shown promising manifestation in improving the survival rate of patients with advanced melanoma, with its efficacy closely linked to Programmed cell death-Ligand 1 (PD-L1) expression. However, low clinical efficacy and drug resistance remain major challenges. Although the metabolic alterations from tricarboxylic acid (TCA) cycle to glycolysis is a hallmark in cancer cells, accumulating evidence demonstrating TCA cycle plays critical roles in both tumorigenesis and treatment.METHODS: The plasma levels of metabolites in patients with melanoma were measured by nuclear magnetic resonance (NMR) spectroscopy. The effect of pyruvate dehydrogenase subunit 1 (PDHA1) and oxoglutarate dehydrogenase (OGDH) on immunotherapy was performed by B16F10 tumor-bearing mice. Flow cytometry analyzed the immune microenvironment. RNA sequencing analyzed the global transcriptome alterations in CPI613-treated melanoma cells. The regulation of PD-L1 and glycolysis by PDHA1/OGDH-ATF3 signaling were confirmed by Quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, dual-luciferase reporter gene, Chromatin immunoprecipitation (ChIP)-quantitative PCR and Seahorse assay. The relationship between PDHA1/OGDH-ATF3-glycolysis and the efficacy of melanoma anti-PD-1 immunotherapy was verified in the clinical database and single-cell RNA-seq (ScRNA-Seq).
RESULTS: In our study, the results showed that significant alterations in metabolites associated with glycolysis and the TCA cycle in plasma of patients with melanoma through NMR technique, and then, PDHA1 and OGDH, key enzymes for regulation TCA cycle, were remarkable raised in melanoma and negatively related to anti-PD-1 efficacy through clinical database analysis as well as ScRNA-Seq. Inhibition of PDHA1 and OGDH by either shRNA or pharmacological inhibitor by CPI613 dramatically attenuated melanoma progression as well as improved the therapeutic efficacy of anti-PD-1 against melanoma. Most importantly, suppression of TCA cycle remarkably raises PD-L1 expression and glycolysis flux through AMPK-CREB-ATF3 signaling.
CONCLUSIONS: Taken together, our results demonstrated the role of TCA cycle in immune checkpoint blockade and provided a novel combination strategy for anti-PD-1 immunotherapy in melanoma treatment.

Keywords:  Immunotherapy; Melanoma

DOI:  https://doi.org/10.1136/jitc-2023-007146
Life Sci. 2023 Sep 02. pii: S0024-3205(23)00698-7. [Epub ahead of print] 122063

MitoQ combats tumor cell progression in Ehrlich ascites carcinoma mice: A crosstalk between mitochondrial oxidative status, mitophagy, and NF-κB signaling.

Mamdouh A Oraby, Ola Elazazy, Heba M Karam, Doaa S Fadaly, Ayman A Ibrahim.

  Despite the clinical advances in cancer treatment, the high mortality rate is still a great challenge, requiring much effort to find new and efficient cancer therapies.AIMS: The present evidence investigated the potential antiproliferative impact of the mitochondrial-targeted antioxidant, Mitoquinol (MitoQ), on a mouse model of Ehrlich ascites carcinoma (EAC).
MAIN METHODS: Mice-bearing tumors were administered two doses of MitoQ (0.3 mg & 0.5 mg/kg; i.p daily) or doxorubicin (2 mg/kg; i.p daily) for 20 days.
KEY FINDINGS: EAC mice revealed exacerbated mitochondrial reactive oxygen species (mtROS) and impaired mitochondrial membrane potential (△Ψm). Dysfunctional mitophagy was observed in EAC mice, along with boosting aerobic glycolysis. In addition, tumor cells exhibited higher proliferation rates, thereby stimulating cell cycle, invasion, and angiogenesis biomarkers together with suppressing proapoptotic proteins, events that might be correlated with activation of NF-κB signaling. The administration of MitoQ combated tumor cell survival and dissemination in EAC mice as evidenced by reducing tumor volumes and weights and increasing the number of necrotic areas in histopathological assessment. MitoQ also repressed tumor cell cycle, invasion, and angiogenesis via preventing cyclin D1 mRNA, MMP-1, and CD34 levels as well as VEGF protein expression. These observations were associated with the abrogation of mtROS overproduction and enhancement of the mitophagy proteins, PINK1/Parkin levels, followed by inhibition of NADH dehydrogenase. Notably, NF-κB signaling was modulated.
SIGNIFICANCE: This study suggests that MitoQ combated tumor cell survival and progression in EAC mice by maintaining mtROS and restoring mitophagy, thereby attenuation of NF-κB activation.

Keywords:  Doxorubicin; Ehrlich ascites carcinoma; MitoQ; Mitophagy; Mitoquinol; Solid tumor

DOI:  https://doi.org/10.1016/j.lfs.2023.122063